The development of chronic tolerance to nicotine (NIC) parallels, and may be causally linked to the development of smoking behavior. Understandably, considerable attention has been given to identify the mechanisms underlying tolerance. Theories relating tolerance to smoking behavior rely heavily on animal models of tolerance to NIC's effects. However, this vast literature has been based, amongst without exception, on experimenter-administered drug. While considerable evidence has been gained using this approach, extrapolation to human use is limited by the assumption that the effects of experimenter-administered (non- contingent) NIC are the same as self-administered (contingent) NIC. This assumption has been questioned recently by research on stimulants and opiates and by our recent data which show striking differences in both the acute and chronic effects of contingent versus non-contingent recent data which show striking differences in both the acute and chronic effects of contingent versus non-contingent NIC. We are focusing on gaps in the literature by determining whether the tolerance (or sensitization) that has been reported for non-contingent NIC is also obtained for self- administered NIC, for those effects that have been hypothesized as being important for the drug's abuse potential and/or health consequences. Using a limited access and triple-yoked paradigm, which contrasts self- administered NIC with non-contingent (yoked) NIC and vehicle, we will ask: (1) Does the induction of tolerance or sensitization by pre-exposure to NIC alter NIC SA in rats? (2) Do the reinforcing effects of NIC exhibit tolerance or sensitization? (3) Does NIC SA induce tolerance or sensitization for behavioral (anti-nociception and locomoter activation), endocrine (elevation of corticosterone) and sympathetic nervous system (increased heart rate, blood pressure and plasma catecholamines) effects previously reported for experimenter-administered NIC? (4) Does NIC SA produce the same changes in nicotinic cholinergic receptors in the brain as has been reported for experimenter-administered NIC?